One-month immunotherapy trial in treatment-failed TB patients

doi:10.4236/oji.2011.12006

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Vol.1, No.2, 50-55 (2011)

doi:10.4236/oji.2011.12006

Open Journal of Immunology

One-month immunotherapy trial in treatment-failed TB

patients

Olga V. Arjanova1, Dmitry A. Butov2, Natalia D. Prihoda1,Svetlana I. Zaitzeva2,

Larisa V. Yurchenko1, Nina I. Sokolenko1, Anna L. Stepanenko2, Tatyana S. Butova2,

Elena A. Grinishina3, Olga A. Maksimenko4, Vichai Jirathitikal5, Aldar S. Bourinbaiar6,

Valery M. Frolov7, Galyna A. Kutsyna7*

1Lisichansk Regional Tuberculosis Dispensary, Lisichan sk, Ukraine;

2Department of Phtysiatry and Pulmonology, Kharkov National Medical University; Kharkov, Ukraine;

3Zmeev Regional Tuberculosis Dispensary, Zmeev, Ukraine;

4Izyum Regional Tuberculosis Dispensary, Izyum, Ukraine;

5Immunitor Thailand Co., LLC, Bangpakong Industrial Park, Chachoengsao, Thailand;

6Immunitor USA Inc., College Park, USA;

7Luhansk State Medical University, Luhansk, Ukraine; *[email protected].

Received 17 August 2011; revised 1 September 2011; accepted 9 September 2011.

ABSTRACT

Treatment failed TB patients have very limited

chances of s urv ival. Open label trial of daily oral

pill of V-5 Immunitor (V5) was conducted in 48

treatment-failed TB patie nts on palliative support

consisting of isoniazid (H) and rifampicin (R).

The subjects had the following forms of TB;

cavit ary : disseminated: MDR-TB: DR-TB: TB/HIV

at 35:13:7:4:1 ratio. After 1 month 62.5% of V5-

treated patients experienced negative sputum

smear conversion (P < 0.0001), comprising 11

out of 12 (91.7%) converted among those who

had drug-resistant TB an d TB/HIV. TB-associated

inflammation was downregulated as evidenced

by normalization of leukocy tosis 7.4 vs. 6.7 x 109

L (P = 0.01) and decr eas e d erythrocyte sedimen-

tation rate 20.5 vs. 14.9 mm/h (P < 0.0001). The

mean body temperature normalized from 37.25˚

± 0.6˚ to 36.98˚ ± 0.4˚ (P = 0.0002). The average

body weight gain and body mass index (BMI)

increased by 0.8 ± 0.7 kg and from 18.9 to 19.6

kg/m2 respectively (P < 0.0001). Two patients

(4.2%) died from illicit drug- and alcohol-abuse

related causes. No adverse effects or reactiva-

tion of disease due to im mune interv ention were

seen at any time. V5 is safe and in combination

with a simple two-drug regimen was highly

effective as an immune adjunct to produce

favorable outcome among treatment-failed and/

or drug-resis tant TB patients.

Keywords: Biomarker; HIV; Inflammat ion; MDR-TB;

Mycobacterium; Survival; Treatment Failure; Vaccine;

1. INTRODUCTION

Mycobacterium tuberculosis is responsible for the

largest number of deaths attributable to a single micro-

organism. Nearly 9 million people develop TB each year

and 2 million die from the disease [1]. Currently avail-

able chemotherapies for treatment of TB are not ideal -

they require multiple tuberculosis drugs to be taken for

long periods of time. The length of therapy, co upled with

side effects, often results in poor patient adherence,

treatment failure, and the emergence of drug resistance

[2]. Current so-called directly observed short-course

(DOTS) chemotherapy requires 6 months; with isoniazid,

rifampicin, pyrazinamide and ethambutol during first 2

months of intensive phase and isoniazid and rifampicin

for continuation phase. The WHO global target for suc-

cessful DOTS is set at 85% or higher, however the

worsening epidemic of drug resistant TB converging

with HIV reduces the likelihood of attaining this goal.

Patients who failed treatment have very few therapeutic

options and mortality and morbidity in this category is

extremely high. If left untreated one year fatality esti-

mate is 70% for smear-positive and 20% for culture-

positive but smear-negative tuberculosis [2]. In a study

involving patients resistant to isoniazid and rifampicin

65% became culture negative but treatment failure, de-

fined as the inability of chemotherapy to sterilize cul-

tures, occurred in almost half of patients (46%) [3]. The

idea that immunotherapy might improve TB treatment

outcomes started gaining consensus in recent years [4].

O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55

5151

Oral therapeutic vaccine V5 Immunitor was originally

developed for the management of chronic hepatitis B and

C [5-7]. The preparation is derived from pooled blood of

HBV- and HCV-positive donors, which following chemi-

cal- and heat inactivation was formulated into an oral pill

according to the proprietary technology developed by us

[7]. During clinical trial in 20 patients with hepatitis C,

who happened to have pulmonary TB with HIV

co-infection, V5 produced mycobacterial clearance in

sputum smears of 94.4% of patients within one month [8].

Due to this surprising outcome a placebo-controlled, ran-

domized phase 2b trial was initiated. Two preliminary

reports from this trial involving initial 88 patients were

already published, confir ming that V5 was safe and con-

sistently enhanced the efficacy of TB drugs [9,10].

In these trials we had a couple of patients who have

repeatedly failed all available therapies and were on

so-called palliative support consisting of isoniazid and

rifampicin only [10]. Despite treatment failure and

seemingly ineffective two-drug combination these pa-

tients became sputum smear negative within one month.

In the present study we expanded this observation by

recruiting 48 treatment-failure patients who received

palliative HR in combination with V5 for one month.

2. MATERIALS AND METHODS

2.1. V5 Immunitor

V5 is derived from the pooled blood of donors with

HBV and HCV, which after heat- and chemical inactiva-

tion was formulated into an oral pill [5-7]. It is well

known that one third of people carry M. tuberculosis

without showing symptoms of the disease—latent TB.

Therefore, V5 inherently comprises circulating antigens

of M. tuberculosis. As we had not known prior to this

accidental discovery that V5 may affect TB we have no

much information regarding the exact content of M. tu-

berculosis antigens. V5 was approved in 2008 by the

Ministry of Health of Ukraine as an immunomodulating

supplement for the management of chronic hepatitis.

2.2. Patients

The conduct of the trial was approved by the internal

review board of th e Lisich ansk TB Disp ensary a nd has a

ClinicalTrials.gov identifier: NCT01222338. The study

involved 48 patients all of whom were treatment failures

and were placed on so-called palliative support consist-

ing of daily isoniazid (H) and rifampicin (R) (Table 1

and Figure 1). This regimen is assigned to very limited

number of patients by the regional h ealth authorities as a

result of case-by-case evaluation of medical and treat-

ment adherence history by specially appointed ethics

committee. Usually these are patients who had repeat-

edly failed to convert after multiple treatment options

had been tried unsuccessfully for an average/median (6

years ± 3.3 years /5 years (range 2 years - 19 years).

Drug and alcohol abuse combined with poor compliance

are common among these patients. The participation in

this study was voluntary and patients were eligible to

enroll only after signing the written consent. The group

had 4 females (8.3%) and 44 males between ages 23 - 68

with mean ± SD (median) age 38.4 years ± 10.9(35.5)

100

Male FemaleTB/HIVDR-TBMDR-TBMiliaryCavitary

% of patients

Figure 1. The proportion of patients at baseline ac-

cording to their gender and diagnosis .

Table 1. Summary of baseline data and treatment outcome in 48 treatment-failed TB patients treated with isoniazid and rifampicin in

combination with V5 for one month.

Body

weight(kg) Body mass

index(kg/m2)Body

temperture(˚C) Hemoglo-

bin(g/L) ESR(mm/h) Leukocytes

(×109L) Sputumsmear

(+/–)

Sex

F/M Age Diagnosis

before after before afterbeforeafterbeforeafterbeforeafter before after beforeafter

57.8

±10.8 58.6

±10.7 18.9

±3 19.7

±3 37.25

±0.6 36.98

±0.4 118.8

±15 118.5

±14.3 20.5

±14.9 14.9

±11.2 7.4

±3.4 6.7

±2.9 48/0 18/30

4/44

Mean

38.4

±10.9

Median

35.5

Miliary TB = 13

Cavitary TB =

MDR-TBa = 7

DR-TBb = 4

TB/HIV = 1 P < 0.0001 P < 0.0001 P = 0.0002 P = 0.78 P < 0.0001 P = 0.013 P < 0.0001

O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55

years. Almost half of patients were underweight (47.9%

with BMI less than 18.5 kg/m2), the baseline body

weight and body mass index (BMI) ranged between 38

kg - 86 kg and 14 - 26.5 with mean ± SD (median) 57.8

kg ± 10.8 (56.5) kg and 18.9 kg/m2 ± 3 (18.6) kg/m2.

This group had one confirmed HIV infection and 7

MDR-TB. Four additional patients had confirmed drug

resistance other than MDR-TB (Table 1). For the re-

maining patients drug resistance profile was unavailable.

Thirteen patients had disseminated or miliary form of

TB (27.1%) and the rest had cavitary disease (72.9%).

Most patients, 29 out of 48 (60.4%), had normal body

temperature at study initiation with overall mean ±

SD/median 37.3˚C ± 0.6˚C/36.8˚C.

2.3. Laboratory Evaluation

The sputum microscopy on acid-fast bacilli (AFB)

smears was conducted in a blinded fashion at baseline

and one month later. TB drug resistance was deter mined

by commercially available kit (Tulip Diagnostics, Goa,

India) in one third of patients. The failure to test every

patient for drug resistance was due to lack of funds for

laboratory services. MDR-TB status was assigned when

resistance to both isoniazid and rifampicin, with or

without resistance to other drugs, was present. DR-TB

was assigned when resistance to drugs other than those

in MDR-TB category was found. The hematology pa-

rameters were evaluated by standard routine techniques at

baseline and repeated one month later.

2.4. Statistical Analysis

The obtained results were analyzed with commercially

available statistical software (GraphPad Software Inc, La

Jolla, CA, USA). The paired Student t-test was used to

compare before-after means by assuming that the distribu-

tion of the differences was in accord with Gaussian dis-

tribution. The Wilcoxon test was used to compare paired

before-after nonparametric values such as conversion

rates arranged in “yes” or “no” binary manner. Fisher’s

exact two-tailed test was employed for analysis of data

arranged in a contingency table. All statistical analyses

were done on intent-to-treat basis, involving all initially

enrolled patients including fatalities. The resulting prob-

ability values were considered as significant at P ≤ 0.05.

3. RESULTS

3.1. Lack of Adverse Reactions

During the entire duration of follow-up no adverse

reactions or reactivation of TB attributable to V5 were

identified. Quite contrary patients who were receiving

chemotherapy along with V5 fared much better. Due to

alcohol and narcotic drugs’ overdose two patients in the

V5 group died during the study but they were not ex-

cluded from the statistical analysis of data, so that the

intent-to-treat design was not compromised. The quanti-

tative endpoints detailed below indicate that the addition

of V5 to anti-tuberculosis therapy (ATT) has resulted in

better clinical outcome.

3.2. Effect On Axillary Body Temperature

The average ± SD (median) body temperature values

were relatively low, i.e., 37.3˚C ± 0.6 (36.8) ˚C. The

proportion of patients with low grade fever was also

small, i.e., 39.6%. At study initiation the proportion of

patients who had normal body temperature of 36.8˚C

was 60.4% which one month later increased to 83.3%

(Figure 2).The overall mean temperature drop was

0.3˚C, i.e., from 37.25˚C ± 0.6˚C to 36.98˚C ± 0.4˚C (P

= 0.0002).

3.3 Effect on Hematology Parameters

The effect of V5 on white blood cells and hematology

parameters are shown in Tab l e 1 and Figure 2. Patients

displayed following positive changes, which resulted

from V5 intervention. Elevated leukocyte counts, tradi-

tionally associated with inflammation, were reduced in

V5-treated group from 7.4 to 6.7 x109/L (P = 0.013). The

decrease was observed in 31 (64.6%) patients, increase

in 10 (20.8%), and in remaining 7 (14.6%) no changes

relative to baseline were seen. Another marker of in-

flammation, the erythrocyte sedimentation rate (ESR),

declined from 20.5 to 14.9 mm/h (P < 0.0001). The fa-

vorable response was seen in 37 (77.1%) individuals and

in remaining 11 patients ESR increased. The content of

hemoglobin has not changed, i.e., 118.8 g/L ± 15 g/L vs.

118.5 g/L ± 14.3 g/L (P = 0.78). Among these 39.6% of

patients had favorable response, one (2.1%) had un-

changed level, and in remaining 28 (58.3%) patients the

hemoglobin content had decreased.

Same

Down

Sam e

Down

Sam e

Down

Sam e

Down

Weight/BMI TemperatureHBESRLeukocytes

% of patien ts

Figure 2. Proportion of patients with three types of outcome in

relation to the weight/body mass index, body temperature,

hemoglobin content (HB), erythrocyte sedimentation rate

(ESR), and leukocyte counts.

O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55

5353

3.4. Effect On Weight and Body Mass Index

Enrolled patients had underweight problem. Accord-

ing to BMI almost half of enrolled patients (47.9%) had

entry level values below normal 18.5 kg/m2; two (4 .2%)

patients were overweight, and the rest were in the nor-

mal range between 18.6 kg/m2 - 25 kg/m2. The mean/

median baseline weight and body mass index were 57.8

kg ± 10.8/56.5 kg and 18.9 kg/m2 ± 3/18.6 kg/m2 respec-

tively. After one month one patient (2.1%) lost 1 kg, 16

patients (33.3%) retained the same weight and in re-

maining 31 (64.6%) patients the increase in body mass

ranged between 1 kg - 2 kg, with average (median) body

weight accrual equal to 0.8 kg ± 0.7 (1.0) kg (P <

0.0001). Changes in body mass index were identical to

variations in the absolute bodyweight (Figure 2). After

the month one patient lost 0.3 kg/m2, 16 patients (33.3%)

retained same BMI, and in remaining 31 (64.6%) pa-

tients the increase ranged b etween 0.2 kg/m2 - 0.9 kg/m2,

with average (median) gain equal to 0.27 kg/m2 ± 0.26

(0.3) kg/m2 reaching values considered to be in the nor-

mal range, i.e., 19.7 ± 3 (19.6) (P < 0.0001).

3.5. Effect on Mycobacterial Clearance

Bacterial clearance was scored in a blinded fashion on

AFB-stained sputum smears as negative/positive scores.

At the end of first month thirty (62.5%) of V5-treated

patients became sputum negative, which was highly sig-

nificant by paired Wilcoxon ranking test (P < 0.0001).

The majority of conver ted patients, 37 out of 48 (70.3%)

had cavitary TB, and remaining converters had dissemi-

nated TB. Eleven out of 12 (91.7%) patients with

MDR-TB, DR-TB and single TB/HIV had converted

after one month. It is of interest that when treat-

ment-failure patients have been stratified according to

the duration of their disease, those who had longer TB

history were converted more readily (Figure 3).

4. DISCUSSION

The results of this one-month immunotherapy study in

treatment-failed TB patients on palliative support, con-

sisting of isoniazid and rifampicin, revealed high nega-

tive sputum conversion rate. These results combined

with additional benefit of enhanced body mass gain,

fever normalization, and potent anti-inflammatory effect

are in line with previously reported favorable responses

due to V5 intervention [8-10]. The fact that we have seen

negative conversion in patients who were unsuccessfully

treated with first- and second-line chemotherapy for 6

years on average and w ere as a consequence giv en up is

perhaps the most impressive outcome of this study.

As new TB drugs are still in pipeline, one of priorities

in TB managem ent i s to find opt im al combinati on am ong

0 255075

1992

1997

1999

2000

2001

2003

2004

2005

2006

2007

2008

2009

1111232116974

No. of patients in each y ear

P ercenta ge

100

Success Failure

Figure 3. Proportion of V5-treated patients at study conclusion

with negative (success) or positive (failure) sputum smear in

relation to the year of TB diagnosis (Y axis).

existing drugs [1,11]. Isoniazid and rifampicin tandem

regimen, introduced in 1970’s, is perhaps best effective

and least toxic combination. However, when resistance

to both drugs arises, treatment is complicated, prolonged,

costly, and outcome is poor. TB treatment failure is

strongly predictive of active MDR-TB and success rates

are rarely better than 65% even when multiple 1st and 2nd

line TB drugs are employed for as long as 12 months -

24 months [3,12,13]. Recently reported DOTS success

rate in former Soviet Union countries in TB patients,

some of whom had MDR-TB and HIV, was 68.1% [14].

However, not every patient enrolled in our study had lab

results from drug-resistance testing. We had 7 and 4

confirmed MDR-TB and DR-TB respectively including

one single patient with HIV; out of these 12 individuals

11 became sputum negative. Even if it may appear at

first sight that we are obtaining similar proportion of

conversion as in literature, our results are not compara-

ble to prior studies since we were able to obtain such a

conversion rate after one month instead of conventional

6 months - 24 months. This implies that immune-based

therapy can contribute to faster favorable response even

when the least-potent combination of TB drugs is em-

ployed, since by definition MDR-TB is refractor y to this

very same H and R combination. It is also of interest th at

all treatment-failure patients who had history of chronic

TB longer than 10 years had converted. Due to small

sample size the latter findings could have been a random

event. Specially tailored, larger, longitudinal studies are

required to determine the extent of the clinical benefit of

V5, which according to our experience spanning over

the last 4 years appears to be equally effective against

treatment-refractory TB and drug-sensitive cases.

The weight accrual during TB therapy has been iden-

tified as a reliable anthropomorphic biomarker of favor-

able treatment outcome that could be readily utilized in

O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55

resource-limited settings [15]. Bernabe-Ortiz et al., [ 16]

have shown that after adjustment for baseline differences,

patients with good outcome gained, after the first month

of treatment, mean 0.9 kg (P < 0.001), whereas those

with poor outcome lost 1.9 kg (P = 0.003). Present re-

sults with V5 closely match findings from Peru study

suggesting that the trend in bodyweight can predict suc-

cess of tuberculosis therapy. The correlation between

body weight and BMI was not surprising either. Body

mass index is equally reflective of severity of disease

and is a risk factor closer associated with death than

even MDR-TB diagnosis. Its improvement in parallel

with weight gain indicates that the benefit of V5 therapy

can be predicted by both categories of wasting meas-

urement. Alcohol and substance abuse have been associ-

ated with poor TB outcome in many studies [17,18] and

was the cause of death in two patients during this study.

We suspect that practically every patient in our group

had this problem but the exact extent of abuse is not

known since most patients were reluctant to disclose

their addictions.

Leukocytosis and high erythrocyte sedimentation rate

are common during active pulmonary TB [19]. These

biomarkers of tuberculosis which reflect the inflamma-

tory response have been predictable of outcome of V5

immunotherapy in this and prior studies. In our patient

population favorable responses were seen when values

of both markers declined. These results are further sup-

ported by the effect of V5 on defervescence. In contrast,

the hemoglobin content, which does not seem to be re-

lated to inflammation, has not been affected by V5.

It has been commonly argued that immunotherapy can

boost TB drugs’ activity and shorten treatment duration

[4,20-23]. As conventional TB drugs have been of little

value in failure cases are there immune-based intervene-

tions that were successful in such a situation? The search

of the medical literature failed to produce any notewor-

thy evidence except our own published study in which

40 end-stage patients with TB and HIV were treated with

multi-herbal immunomodulator, Dzherelo (Immunoxel)

[24]. This intervention resulted in 65% negative sputum

conversion r ate as opposed to 5% in the contro l. Despite

best possible care 6 patients had died in Immunoxel arm.

Remaining 14 patients experienced clinical improve-

ments and one patient was discharged due to full recov-

ery. Among 20 matched subjects on conventional TB

regimen, 12 died and only one had shown some clinical

improvement (P = 0.001; OR 2.6 at 95% CI 1.5 - 4.7).

While patient population in th at study was not compara-

ble to ours and sample sizes were small, we and our col-

laborators in Uk raine h ave work ed o n immuno th erapy o f

TB and HIV over the past 10 years, which resulted in a

dozen published trials involving about 1,200 individuals

[25]. This extensive experience is summarized as fol-

lows. Typical sputum conversion rate among MDR,

XDR and TB/HIV patients after 2 months - 4 months of

herbal immunotherapy was in 85% - 100% range, while

in chemotherapy controls it took 6 months - 24 months

to reach 48% - 85%. What is remarkable is that very

same clinical manifestations, i.e., inflammation, fever,

and wasting improved in a manner strikingly similar to

V5. This suggests to us that a successful immunotherapy

of any kind ought to produce clinical response that dis-

plays similar, if not identical trend, with these endpoints.

This conclusion is supported by results of numerous

trials of Mycobacterium vaccae, the WH O recommende d

immunotherapy for TB [4], in which sputum conversion

was invariably accompanied by weight gain and de-

creased ESR [26].

Despite many limitations of this study it is clear that

the combination of V5 with stripped-down TB regimen,

consisting of isoniazid and rifampicin only, produces

favorable outcome in treatment-failed TB including

drug-resistant TB and TB/HIV. V5 was safe; no reactiva-

tion of TB was seen at any time, which perhaps is due to

potent anti-inflammatory activity. Immune intervention

such as V5 needs to be tried independently by investiga-

tors in other countries so that simple and safe treatment

for TB is available sooner, especially to those who have

exhausted all treatment options.

5. ACKNOWLEDGEMENTS

We thank all volunteers who participated in this study. The whole-

hearted support of clinicians, nurses and lab personnel who contributed

their effort made this study possible. Our gratitude is expressed to

too-many-to-list experts in TB who kindly shared with us their opin-

ions and critique s prior to and after this study was completed.

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